Wiesner nevusD22L

Solitary or multiple, slow-growing benign melanocytic neoplasms characterized by inactivating mutations of the BAP1 gene. These nevi may be hallmarks of the rare familial tumor predisposition syndrome (OMIM:614327), which is caused by inactivating germline mutations of BAP1 and is associated with atypical Spitz tumors/melanocytic atypical intradermal tumors, cutaneous and uveal melanomas, and internal neoplasms (e.g., mesothelioma, clear cell renal carcinoma, lung adenocarcinoma, squamous cell carcinoma of the head and neck, breast carcinoma, myelodysplasia, medulloblastoma and meningioma).

The tumor suppressor gene BAP1 encodes a deubiquitinase enzyme that is involved in various cellular activities, including DNA repair and apoptosis. The nuclear deubiquitinase BAP1 (BRCA1-associated protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor whose germline variants predispose to cancer with loss of function. It is noteworthy that there are very rare examples of different germline variants of the same gene causing either a neurodevelopmental disorder (Kury-Isidor syndrome) or a tumor predisposition syndrome (Bap1 tumor predisposition syndrome) (Küry S et al. 2022).

Detection of dermal nests with epithelioid cells with oval to kidney-shaped nuclei and abundant eosinophilic, often inclusion-like cytoplasm. The neoplastic cells show a loss of constitutive nuclear immunostaining for the BAP1 protein and are positive for the VE1 antibody (anti-BRAFV600 mutant protein).

Note: Biallelic inactivating mutations of the BAP1 tumor suppressor gene on chromosome 3p21.1 and loss of nuclear immunoreactivity for the BAP1 protein are characteristic of BAPomas,1 which account for 0.005% of all excised melanocytic tumors. They range from completely benign (e.g. Wiesner's nevus) to melanocytic atypical intradermal borderline tumors to overt malignant tumors. A BRAFV600E mutation, which can be detected with VE1 immunostaining, is present in around 70 % of BAPomas (Ferrara G et al. 2017).

Any cutaneous papulonodular lesion found to be growing should be excised. If a Wiesner nevus is diagnosed histopathologically and is associated with multiple cutaneous (fibroma-like) melanocytic tumors, the patient should be tested for a genetic tumor predisposition syndrome!

1. Ferrara G et al (2017) Wiesner nevus. CMAJ. 2017 Jan 9;189(1):E26.
2. Hafner C (2014) Wiesner nevus: A new molecularly genetically defined melanocytic tumor Dermatology 65:653-655.
3. Küry S et al. (2022) Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder. Am J Hum Genet 109:361-372.
4. Rai K et al. (2016) Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases. Clin Genet 89:285-294.
5. Somogyi M et al. (2024) Wiesner Nevus of the Eyelid. Ophthalmic Plast Reconstr Surg 34:e13-e16.
6. West EC et al. (2024) BRCA1-associated protein 1: Tumor predisposition syndrome and Kury-Isidor syndrome, from genotype-phenotype correlation to clinical management. Clin Genet. 2024 Jun;105(6):589-595.
7. Wiesner T et al. (2011) Germline mutations in BAP1 predispose to melanocytic tumors. Nat Genet 43: 1018-1021.
8. Wiesner T et al. (2016) Genomic aberrations in spitzoid melanocytic tumors and their implications for diagnosis, prognosis and therapy. Pathology 48:113-131.